(W1147) SINGLE CELL ANALYSIS OF HUMAN IPSC-DERIVED NEURONS CARRYING THE ALZHEIMER DISEASE-ASSOCIATED APPV717I MUTATION AFTER LONG-TERM ENGRAFTMENT IN THE ADULT MOUSE FOREBRAIN

Abstract: Alzheimer’s disease (AD) is the most frequent form of dementia affecting millions of people without a cure, and disease mechanisms are still not fully understood. Here, we applied a human-to-mouse xenotransplantation approach to assess histological alterations and changes in gene expression in human induced pluripotent stem cell (iPSC)-derived AD neurons at 2 and 12 months post injection into the mouse brain in comparison to transplanted control neurons. To this end, we differentiated human iPSCs carrying the familial AD APPV717I mutation into neurons, which demonstrated enhanced Aβ42 production, elevated phospho-tau, and impaired neurite outgrowth in vitro. After injection into the forebrain of immunocompromised mice, APPV717I or isogenic control neural progenitor cells differentiated into NeuN-positive neurons representing about 90% of cells in both APPV717I and control grafts at 2 months post injection. 12 months after injection however, APPV717I grafts were significantly smaller and contained an increased number of phospho-tau-positive neurons. We performed comparative single-nucleus RNA-sequencing of microdissected APPV717I and control grafts at 2 and 12 months post injection, and found shifts in the cellular composition of grafts with an enrichment of cell death pathways in APPV717I neurons at 12 months post injection, which were not seen in control neurons at that time point or in APPV717I neurons 2 months after injection. These data give important insights into transcriptional dysregulation in human APPV717I neurons linked to cellular vulnerability in vivo and provide a unique opportunity to study potentially beneficial effects of therapeutic compounds in this xenograft disease model.

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